title: Combined acute hyperglycemic and hyperinsulinemic clamp induced profibrotic and proinflammatory responses in the kidney.
abstract: Increase in matrix protein content in the kidney is a cardinal feature of diabetic kidney disease. While renal matrix protein content is increased by chronic hyperglycemia, whether it is regulated by acute elevation of glucose and insulin has not been addressed. In this study, we aimed to evaluate whether short duration of combined hyperglycemia and hyperinsulinemia, mimicking the metabolic environment of prediabetes and early type 2 diabetes, induces kidney injury. Normal rats were subjected to either saline infusion (control, n = 4) or 7 h of combined hyperglycemic-hyperinsulinemic clamp (HG+HI clamp; n = 6). During the clamp, plasma glucose and plasma insulin were maintained at about 350 mg/dl and 16 ng/ml, respectively. HG+HI clamp increased the expression of renal cortical transforming growth factor-β (TGF-β) and renal matrix proteins, laminin and fibronectin. This was associated with the activation of SMAD3, Akt, mammalian target of rapamycin (mTOR) complexes, and ERK signaling pathways and their downstream target events in the initiation and elongation phases of mRNA translation, an important step in protein synthesis. Additionally, HG+HI clamp provoked renal inflammation as shown by the activation of Toll-like receptor 4 (TLR4) and infiltration of CD68-positive monocytes. Urinary F2t isoprostane excretion, an index of renal oxidant stress, was increased in the HG+HI clamp rats. We conclude that even a short duration of hyperglycemia and hyperinsulinemia contributes to activation of pathways that regulate matrix protein synthesis, inflammation, and oxidative stress in the kidney. This finding could have implications for the control of short-term rises in blood glucose in diabetic individuals at risk of developing kidney disease.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas;
authors.forename: Meenalakshmi M
authors.initials: MM
authors.lastname: Mariappan
authors.forename: Kristin
authors.initials: K
authors.lastname: DeSilva
authors.forename: Gian Pio
authors.initials: GP
authors.lastname: Sorice
authors.forename: Giovanna
authors.initials: G
authors.lastname: Muscogiuri
authors.forename: Fabio
authors.initials: F
authors.lastname: Jimenez
authors.forename: Seema
authors.initials: S
authors.lastname: Ahuja
authors.forename: Jefferey L
authors.initials: JL
authors.lastname: Barnes
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.forename: Ralph
authors.initials: R
authors.lastname: DeFronzo
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism; D004789:Enzyme Activation; D005353:Fibronectins / Q000096:biosynthesis; D005355:Fibrosis; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology*; D006946:Hyperinsulinism / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007797:Laminin / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001786:Blood Glucose; D005353:Fibronectins; D007797:Laminin; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D051900:Smad3 Protein; D058570:TOR Serine-Threonine Kinases; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C497787:Smad3 protein, rat; C495347:Tlr4 protein, rat; C546845:mTOR protein, rat
keywords: TGF-β; hyperglycemia; hyperinsulinemia; laminin; mTOR; renal fibrosis